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Effects of 2'-Deoxycoformycin Infusion on Mouse Adenosine Deaminase¹

Memorial Sloan-Kettering Cancer Center, New York, New York 10021

The effect of 2'-deoxycoformycin (DCF) on activity levels and physicochemical properties of mouse adenosine deaminase (ADase) and purine nucleoside phosphorylase from nine tissues was characterized. This tight-binding inhibitor of ADase was continuously infused into C57BL mice for five days. Various levels of ADase which were tissue dependent remained after this period. Thymus activity was the most severely inhibited; jejunum, ileum, and spleen activities were only marginally depressed; and stomach activity was not inhibited. The presence of a transplantable colon tumor resulted in significantly lower ADase after infusion, especially in jejunum. Tumor ADase was depressed to approximately 15% of the control value. The extent of inhibition was found to be dependent on the mouse strain, i.e., ADase from tissues of CD-1 mice was generally inhibited to a greater extent than was enzyme from the C57BL strain. Levels of purine nucleoside phosphorylase were relatively insensitive to the infusion. With the exception of the thymus, in vitro inhibition of ADase by DCF exceeded that produced in vivo. Residual levels of activity remaining in both cases were generally less sensitive to inhibition by DCF than untreated enzyme. Ackermann-Potter plots establish the inhibition as stoichiometric both before and after DCF infusion and provide evidence for a significant decrease in affinity after infusion. The data suggest the possibility of the induction of a form of ADase less sensitive to inhibition than is native enzyme. These results may be of eventual usefulness in the design of combined chemotherapeutic regimens involving adenosine analogs and tight-binding inhibitors.

¹ This research was supported by USPHS Grant CA-14906 from the National Cancer Institute through the National Large Bowel Cancer Project, by USPHS Grants CA-18856 and CA-18428, and by Grant BC 202B from the American Cancer Society.

² To whom requests for reprints should be addressed. Recipient of American Cancer Society Faculty Research Award FRA 182.

Received 9/13/78. Accepted 4/24/79.